Abstract
PEGylation typically improves the systemic exposure and tumor biodistribution of polymeric drug delivery systems, but may also restrict enzyme access to peptide-based drug linkers. The impact of dendrimer generation (G4 vs G5) and PEG length (570 vs 1100 Da) on the pharmacokinetics, tumor biodistribution, drug release kinetics, and anticancer activity of a series of PEGylated polylysine dendrimers conjugated with doxorubicin via a cathepsin-B cleavable valine-citrulline linker was therefore investigated in rodents. Although the smallest G4 PEG570 dendrimer showed the most efficient cathepsin-mediated doxorubicin release, systemic exposure and tumor uptake were limited. The largest G5 PEG1100 dendrimer showed good tumor uptake and retention but restricted drug liberation and therefore limited anticancer activity. Superior anticancer activity was achieved using an intermediate sized dendrimer that showed better drug release kinetics, systemic exposure, tumor uptake, and retention. The data suggest that balancing PEG molecular weight and dendrimer size is critical when designing chemotherapeutic dendrimers.
| Original language | English |
|---|---|
| Pages (from-to) | 4568-4576 |
| Number of pages | 9 |
| Journal | Molecular Pharmaceutics |
| Volume | 15 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - 1 Oct 2018 |
Keywords
- biodistribution
- cathepsin B
- dendrimer
- pharmacokinetics
- tumor
Cite this
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Reducing Dendrimer Generation and PEG Chain Length Increases Drug Release and Promotes Anticancer Activity of PEGylated Polylysine Dendrimers Conjugated with Doxorubicin via a Cathepsin-Cleavable Peptide Linker. / Mehta, Dharmini; Leong, Nathania; McLeod, Victoria M.; Kelly, Brian D.; Pathak, Rashmi; Owen, David J.; Porter, Christopher J.H.; Kaminskas, Lisa M.
In: Molecular Pharmaceutics, Vol. 15, No. 10, 01.10.2018, p. 4568-4576.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Reducing Dendrimer Generation and PEG Chain Length Increases Drug Release and Promotes Anticancer Activity of PEGylated Polylysine Dendrimers Conjugated with Doxorubicin via a Cathepsin-Cleavable Peptide Linker
AU - Mehta, Dharmini
AU - Leong, Nathania
AU - McLeod, Victoria M.
AU - Kelly, Brian D.
AU - Pathak, Rashmi
AU - Owen, David J.
AU - Porter, Christopher J.H.
AU - Kaminskas, Lisa M.
PY - 2018/10/1
Y1 - 2018/10/1
N2 - PEGylation typically improves the systemic exposure and tumor biodistribution of polymeric drug delivery systems, but may also restrict enzyme access to peptide-based drug linkers. The impact of dendrimer generation (G4 vs G5) and PEG length (570 vs 1100 Da) on the pharmacokinetics, tumor biodistribution, drug release kinetics, and anticancer activity of a series of PEGylated polylysine dendrimers conjugated with doxorubicin via a cathepsin-B cleavable valine-citrulline linker was therefore investigated in rodents. Although the smallest G4 PEG570 dendrimer showed the most efficient cathepsin-mediated doxorubicin release, systemic exposure and tumor uptake were limited. The largest G5 PEG1100 dendrimer showed good tumor uptake and retention but restricted drug liberation and therefore limited anticancer activity. Superior anticancer activity was achieved using an intermediate sized dendrimer that showed better drug release kinetics, systemic exposure, tumor uptake, and retention. The data suggest that balancing PEG molecular weight and dendrimer size is critical when designing chemotherapeutic dendrimers.
AB - PEGylation typically improves the systemic exposure and tumor biodistribution of polymeric drug delivery systems, but may also restrict enzyme access to peptide-based drug linkers. The impact of dendrimer generation (G4 vs G5) and PEG length (570 vs 1100 Da) on the pharmacokinetics, tumor biodistribution, drug release kinetics, and anticancer activity of a series of PEGylated polylysine dendrimers conjugated with doxorubicin via a cathepsin-B cleavable valine-citrulline linker was therefore investigated in rodents. Although the smallest G4 PEG570 dendrimer showed the most efficient cathepsin-mediated doxorubicin release, systemic exposure and tumor uptake were limited. The largest G5 PEG1100 dendrimer showed good tumor uptake and retention but restricted drug liberation and therefore limited anticancer activity. Superior anticancer activity was achieved using an intermediate sized dendrimer that showed better drug release kinetics, systemic exposure, tumor uptake, and retention. The data suggest that balancing PEG molecular weight and dendrimer size is critical when designing chemotherapeutic dendrimers.
KW - biodistribution
KW - cathepsin B
KW - dendrimer
KW - pharmacokinetics
KW - tumor
UR - http://www.scopus.com/inward/record.url?scp=85052339085&partnerID=8YFLogxK
U2 - 10.1021/acs.molpharmaceut.8b00581
DO - 10.1021/acs.molpharmaceut.8b00581
M3 - Article
VL - 15
SP - 4568
EP - 4576
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
SN - 1543-8384
IS - 10
ER -